1-(2H-1-oxo-3,4-dihydronaphtyl-6-yl)-acetyl-piperidines as kappa agonists

ABSTRACT

##STR1##   Azacyclic derivatives of formula (I), in which R 1  and R 2  are each linear or branched alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, cycloalkenyl or alkynyl; R 3  and R 4  are identical, and each is a hydrogen or alkyl; and R 5  is hydrogen or alkyl, and their use in medicine are disclosed.

This invention is concerned with novel azacyclic derivatives, processesfor their preparation, and their use in medicine.

Compounds which are kappa-receptor agonists act as analgesics throughinteraction with kappa opioid receptors. The advantage of kappa-receptoragonists over the classical μ-receptor agonists, such as morphine, liesin their ability to cause analgesia while being devoid of morphine-likebehavioural effects and addiction liability.

European Published Application Nos. 333315 and 361791 disclose groups ofazacyclic derivatives which exhibit kappa-receptor agonism without someof the behavioural effects of morphine and morphine analogues, and whichare thus of potential therapeutic utility as analgesics.

Certain azacyclic derivatives falling within the scopes of the aboveEuropean Applications, but not specifically disclosed therein, have nowbeen discovered which also exhibit potent kappa-receptor agonism and arepotentially useful as analgesics, including peripheral analgesics fortreating inflammatory pain.

These derivatives show a diminished affinity for kappa brain receptorswhile retaining effective analgesic activity. The derivatives are alsoof potential use in the treatment of cerebral ischaemia.

According to the present invention there is provided a compound, or asolvate or salt thereof, of (I): ##STR2## in which: R₁ and R₂ are eachlinear or branched C₃₋₄ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ cyclcalkylalkyl,C₃₋₄ alkenyl, C₃₋₆ cycloalkenyl or C₃₋₄ alkynyl,

R₃ and R₄ are identical, and each is hydrogen or C₁₋₄ alkyl; and

R₅ is hydrogen or C₁₋₃ alkyl.

Preferably, when R₃ and R₄ are C₁₋₄ alkyl they are both bonded to thesame carbon atom of the piperidine ring, thereby forming a gem-dialkylgrouping.

When R₅ is C₁₋₃ alkyl, R₃ and R₄ are preferably hydrogen.

Examples of R₁ and R₂ are methyl, ethyl, propyl, isopropyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, allyl, andpropynyl.

Examples of R₃ and R₄ are hydrogen, 3,3 gem-dimethyl, 4,4 gem-dimethyland 5,5 gem-dimethyl. Examples of R₅ are hydrogen and methyl.

The compounds of formula I or their salts or solvates are preferably inpharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, of apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels.

A substantially pure form will generally contain at least 50% (excludingnormal pharmaceutical additives), preferably 75%, more preferably 90%and still more preferably 95% of the compound of formula I or its saltor solvate.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in a pharmaceutical composition. In the case ofsalts and solvates the additional ionic and solvent moieties must alsobe non-toxic.

Examples of a pharmaceutically acceptable salt of a compound of formulaI include the acid addition salts with the conventional pharmaceuticalacids, for example, maleic, hydrochloric, hydrobromic, phosphoric,acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric,succinic, benzoic, ascorbic and methanesulphonic.

Examples of pharmaceutically acceptable solvates of a compound offormula I include hydrates.

The compounds of formula I have an asymmetric centre and therefore existin more than one stereoisomeric form. The invention extends to all suchforms and to mixtures thereof, including racemates.

The present invention also provides a process for the preparation of acompound of formula I which comprises reacting a compound of formula(II): ##STR3## in which R₁, R₂, R₃, R₄, and R₅ are as defined forformula (I), with a compound of formula (III): ##STR4## or an activederivative thereof, and then optionally forming a salt and/or solvate ofthe obtained compound of formula (I).

Suitable active derivatives of the compound of formula (III) are theacid chloride or acid anhydride. Another suitable derivative is a mixedanhydride formed between the acid and an alkyl chloroformate.

For example, in standard methods well known to those skilled in the art,the compound of formula (II) may be coupled:

a) with an acid chloride in the presence of an inorganic or organicbase,

b) with the acid in the presence of dicyclohexyl carbodiimide,N-dimethylaminopropyl-N'-ethyl carbodiimide or carbonyl diimidazole,

c) with a mixed anhydride generated in situ from the acid and an alkyl(for example ethyl)chloroformate.

The compounds of formula I may be converted into their pharmaceuticallyacceptable acid addition salts by reaction with the appropriate organicor mineral acids. Solvates of the compounds of formula I may be formedby crystallization or recrystallization from the appropriate solvent.For example hydrates may be formed by crystallization orrecrystallization from aqueous solutions, or solutions in organicsolvents containing water.

Also salts or solvates of the compounds of formula I which are notpharmaceutically acceptable may be useful as intermediates in theproduction of pharmaceutically acceptable salts or solvates. Accordinglysuch salts or solvates also form part of this invention.

As mentioned before, the compounds of formula I exist in more than onestereoisomeric form and the processes of the invention produces mixturesthereof. The individual isomers may be separated one from another byresolution using an optically active acid such as tartaric acid.Alternatively, an asymmetric synthesis would offer a route to theindividual form.

Compounds of formula (II) may be prepared according to the followingreaction Scheme I: ##STR5## In this scheme, an acid of formula (VI) isfirstly nitrogen-protected with an ethoxycarbonyl protecting group toform a compound of formula (V) which is then reacted with an amine NHR₁R₂ (in which R₁ and R₂ are as defined earlier) to obtain anN-deprotected amide of formula (IV). This amide is then reduced to adiamine of formula (II) by conventional means.

Alternatively, compounds of formula (II) may be prepared according tothe following reaction Scheme II: ##STR6## In this Scheme, a compound offormula (VIII) is treated with a secondary amine NHR₁ R₂ (in which R₁and R₂ are as defined earlier) in the presence of a reducing hydride,such as NaCNBH₃, to form a compound of formula (VII). The latter is thenreduced catalytically using hydrogen/PtO₂ to form a diamine of formula(II).

The compounds of formulae (VII), (VI), (V) and (IV) are generically orspecifically disclosed in the above mentioned European Application No.361791.

The compounds of formula (VIII) are known compounds or can be preparedfrom known compounds by known methods, such as those disclosed in Chem.Berichte 34,4253; J. Org. Chem. 26(1961), 4415; J. Am. Chem. Soc.78(1956), 5842.

The compound of formula (III) and its active derivatives, ashereinbefore defined, are also known compounds, and are disclosed inEP-A-333315.

The activity of the compounds of formula (I) in standard tests indicatesthat they are of potential therapeutic utility in the treatment of painand of cerebral ischaemia.

Accordingly the present invention also provides a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, for useas an active therapeutic substance.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt or solvate thereof, in themanufacture of a medicament for the treatment of pain, or in themanufacture of a medicament for the treatment of cerebral ischaemia.

Such a medicament, and a composition of this invention, may be preparedby admixture of a compound of the invention with an appropriate carrier.It may contain a diluent, binder, filler, disintegrant, flavouringagent, colouring agent, lubricant or preservative in conventionalmanner.

These conventional excipients may be employed for example as in thepreparation of compositions of known analgesic agents or agents for thetreatment of cerebral ischaemia.

Preferably, a pharmaceutical composition of the invention is in unitdosage form and in a form adapted for use in the medical or veterinarialfields. For example, such preparations may be in a pack form accompaniedby written or printed instructions for use as an agent in the treatmentof pain or for the treatment of cerebral ischaemia.

The suitable dosage range for the compounds of the invention depends onthe compound to be employed and on the condition of the patient. It willalso depend, inter alia, upon the relation of potency to absorbabilityand the frequency and route of administration.

The compound or composition of the invention may be formulated foradministration by any route, and is preferably in unit dosage form or ina form that a human patient may administer to himself in a singledosage. Advantageously, the composition is suitable for oral, rectal,topical, parenteral, intravenous or intramuscular administration.Preparations may be designed to give slow release of the activeingredient.

Compositions may, for example, be in the form of tablets, capsules,sachets, vials, powders, granules, lozenges, reconstitutable powders, orliquid preparations, for example solutions or suspensions, orsuppositories.

The compositions, for example those suitable for oral administration,may contain conventional excipients such as binding agents, for examplesyrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone;fillers, for example lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; tabletting lubricants, for example magnesiumstearate; disintegrants, for example starch, polyvinyl-pyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable setting agents such as sodium laurylsulphate.

Solid compositions may be obtained by conventional methods of blending,filling tabletting or the like. Repeated blending operations may be usedto distribute the active agent throughout those compositions employinglarge quantities of fillers. When the composition is in the form of atablet, powder, or lozenge, any carrier suitable for formulating solidpharmaceutical compositions may be used, examples being magnesiumstearate, starch, glucose, lactose, sucrose, rice flour and chalk.Tablets may be coated according to methods well known in normalpharmaceutical practice, in particular with an enteric coating. Thecomposition may also be in the form of an ingestible capsule, forexample of gelatin containing the compound, if desired with a carrier orother excipients.

Compositions for oral administration as liquids may be in the form of,for example, emulsions, syrups, or elixirs, or may be presented as a dryproduct for reconstitution with water or other suitable vehicle beforeuse. Such liquid compositions may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel, hydrogenated edible fats; emulsifying agents, for examplelecithin, sorbitan monooleate, or acacia; aqueous or non-aqueousvehicles, which include edible oils, for example almond oil,fractionated coconut oil, oily esters, for example esters of glycerine,or propylene glycol, or ethyl alcohol, glycerine, water or normalsaline; preservatives, for example methyl or propyl p-hydroxybenzoate orsorbic acid; and if desired conventional flavouring or colouring agents.

The compounds of this invention may also be administered by a non-oralroute. In accordance with routine pharmaceutical procedure, thecompositions may be formulated, for example for rectal administration asa suppository. They may also be formulated for presentation in aninjectable form in an aqueous or non-aqueous solution, suspension oremulsion in a pharmaceutically acceptable liquid, e.g. sterilepyrogen-free water or a parenterally acceptable oil or a mixture ofliquids. The liquid may contain bacteriostatic agents, anti-oxidants orother preservatives, buffers or solutes to render the solution isotonicwith the blood, thickening agents, suspending agents or otherpharmaceutically acceptable additives. Such forms will be presented inunit dose form such as ampoules or disposable injection devices or inmulti- dose forms such as a bottle from which the appropriate dose maybe withdrawn or a solid form or concentrate which can be used to preparean injectable formulation.

As mentioned earlier, the effective dose of compound depends on theparticular compound employed, the condition of the patient and on thefrequency and route of administration. A unit dose will generallycontain from 20 to 1000 mg and preferably will contain from 30 to 500mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.The composition may be administered once or more times a day for example2, 3 or 4 times daily, and the total daily dose for a 70 kg adult willnormally be in the range 100 to 3000 mg. Alternatively the unit dosewill contain from 2 to 20 mg of active ingredient and be administered inmultiples, if desired, to give the preceding daily dose.

Within the above indicated dosage range, no adverse toxicologicaleffects are observed with compounds of the invention.

The present invention also provides a method for the treatment and/orprophylaxis of pain and/or cerebral ischaemia in mammals, particularlyhumans, which comprises administering to the mammal in need of suchtreatment and/or prophylaxis an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof.Compounds of this invention and their preparation are illustrated in thefollowing Examples and compounds of the Examples are summarised in TableI. The pharmacological data are summarised in Table II.

EXAMPLE 1

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethyl-aminomethylpiperidine hydrochloride.

2.0 g (14.08 mmoles) of (2S)-2-dimethylaminomethyl piperidine weredissolved in 50 ml of dry chloroform. 1.94 g (14.06 mmoles) of anhydrouspotassium carbonate were added and the mixture cooled at -10° C. 3.6 g(16.17 mmoles) of crude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetylchloride [obtained from 3.3 g of 1-oxo-3,4-dihydro-(2H)-napht-6-ylacetic acid as described in EP-0333315] dissolved in 20 ml of drychloroform, were added dropwise and the reaction mixture allowed toreach room temperature. After three hours 30 ml of water were added andthe resulting biphasic solution stirred for additional 30'. Theseparated organic layer was washed with water, dried over Na₂ SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on 230-400 mesh silica gel, eluting with a mixture of CH₂Cl₂ /MeOH/28% NH₄ OH, 94:4.5:0.4 respectively, to afford 2.6 g of thefree base, which was dissolved in 50 ml of acetone and the solutionbrought to acidic pH with HCl/Et₂ O. The precipitate was filtered,washed and dried, to yield 2.3 g of the title compound.

C₂₀ H₂₈ N₂ O₂.HCl M.P.=208°-210° C. M.W.=364.905 [α]_(D) ²⁰ =-64.0 (C=1,MeOH) Elemental analysis: Calcd. C,65.83; H,8.01; N,7.68; Cl,9.72; FoundC,65.32; H,7.98; N,7.53; Cl,9.54. I.R. (KBr): 3450; 2950; 1680; 1625;1605 cm⁻¹ N.M.R. (CDCl₃): δ11.80 (s broad, 1H); 8.00 (d, 1H); 7.05-7.4080 MHz (m, 2H); 5.10-5.45 (m, 1H); 3.10-4.30 (m, 5H); 2.40-3.10 (m,11H); 1.90-2.30 (m, 2H); 1.10-1.85 (m, 6H).

EXAMPLE 2

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-ethyl)aminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.1 g (7.04 mmoles) of(2S)-2-(N-methyl-N-ethyl)aminomethyl piperidine, 1.0 g (7.24 mmoles) ofanhydrous potassium carbonate and 1.8 g (8.09 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:6:0.5 respectively, to afford 1.2 g of the free base, whichwas dissolved in 30 ml of acetone and the solution brought to acidic pHwith HCl/Et₂ O. The precipitate was filtered, washed and dried, to yield0.9 g of the title compound.

C₂₁ H₃₀ N₂ O₂.HCl M.P.=163°-165° C. M.W.=378.931 [α]_(D) ²⁰ =-62.5 (C=1,MeOH) Elemental analysis: Calcd. C,66.56; H,8.25; N,7.39; Cl,9.36; FoundC,66.34; H,8.29; N,7.28; Cl,9.23. I.R. (KBr): 3440; 2950; 1680; 1630;1610 cm⁻¹ N.M.R. (CDCl₃): δ11.75 (s broad, 1H); 8.00 (d, 1H); 7.10-7.3080 MHz (m, 2H); 5.10-5.40 (m, 1H); 2.50-4.25 (m, 15H); 1.90-2.20 (m,2H); 1.20-1.80 (m, 9H).

EXAMPLE 3

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-diethylaminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.0 g (5.87 mmoles) of(2S)-2-diethylaminomethyl piperidine, 0.83 g (6.01 mmoles) of anhydrouspotassium carbonate and 1.5 g (6.75 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 35 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:5:0.5 respectively, to afford 800 mg of the free base, whichwas dissolved in 30 ml of ethyl acetate, containing 5% of acetone, andthe solution was brought to acidic pH with HCl/Et₂ O. The precipitatewas filtered, washed and dried, to yield 600 mg of the title compound.

C₂₂ H₃₂ N₂ O₂.HCl M.P.=136°-137° C. M.W.=392.957 [α]_(D) ²⁰ =61.6 (C=1,MeOH) Elemental analysis: Calcd. C,67.24; H,8.47; N,7.13; Cl,9.02; FoundC,66.65; H,8.30; N,7.00; Cl,8.98. I.R. (KBr): 3440; 2955; 1685; 1620;1610 cm⁻¹

EXAMPLE 4

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-3,3-dimethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.53 g (9.0 mmoles) of(±)-2-dimethylaminomethyl-3,3-dimethyl piperidine, 1.2 g (9.2 mmoles) ofanhydrous potassium carbonate and 2.0 g (9.2 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:6:0.5 respectively, to afford 1.2 g of the free base, whichwas dissolved in 30 ml of ethyl acetate and the solution brought toacidic pH with HCl/Et₂ O. The precipitate was filtered, washed anddried, to yield 0.4 g of the title compound.

C₂₂ H₃₂ N₂ O₂.HCl M.P.=253°-255° C. M.W.=392.957 Elemental analysis:Calcd. C,67.23; H,8.46; N,7.13; Cl,9.02; Found C,65.95; H,8.19; N,7.00;Cl,8.98. I.R. (KBr): 3440; 2950; 1685; 1620; 1605 cm⁻¹ N.M.R. (CDCl₃):δ12.1-11.1 (s broad, 1H); 8.1-7.9 (m, 1H); 80 MHz 7.4-7.1 (m, 2H);4.9-4.6 (m, 1H); 4.2-3.1 (m, 5H); 3.1-2.8 (m, 9H); 2.8-1.9 (m, 4H);1.6-1.1 (m, 4H); 1.1-0.7 (m, 6H).

EXAMPLE 5

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-4,4-dimethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 0.7 g (4.11 mmoles) of(±)-2-dimethylaminomethyl-4,4-dimethyl piperidine, 0.57 g (4.2 mmoles)of anhydrous potassium carbonate and 1.0 g (4.2 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 30 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:5:0.5 respectively, to afford 0.9 g of the free base, whichwas dissolved in 20 ml of ethyl acetate and the solution brought toacidic pH with HCl/Et₂ O. The precipitate was filtered, washed anddried, to yield 0.3 g of the title compound.

C₂₂ H₃₂ N₂ O₂.HCl M.P.=214°-216° C. M.W.=392.957 Elemental analysis:Calcd. C,67.23; H,8.46; N,7.13; Cl,9.02; Found C,64.00; H,8.14; N,6.68;Cl,8.65. I.R. (KBr): 3440; 2955; 1685; 1625; 1605 cm⁻¹ N.M.R. (CDCl₃):δ12.1-11.5 (s broad, 1H); 8.0-7.8 (m, 1H); 80 MHz 7.3-7.0 (m, 2H);5.2-4.8 (m, 1H); 4.2-3.2 (m, 5H); 3.0-2.7 (m, 9H); 2.7-1.8 (m, 4H);1.6-1.1 (m, 4H); 0.9 (ds, 6H).

EXAMPLE 6

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-5,5-dimethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.0 g (5.9 mmoles) of(±)-2-dimethylaminomethyl-5,5-dimethyl piperidine, 1.0 g (6.5 mmoles) ofanhydrous potassium carbonate and 1.6 g (6.5 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:5:0.5 respectively, to afford 1.1 g of the free base, whichwas dissolved in 30 ml of ethyl acetate and the solution brought toacidic pH with HCl/Et₂ O. The precipitate was filtered, washed anddried, to yield 0.4 g of the title compound.

C₂₂ H₃₂ N₂ O₂.HCl M.P.=188°-190° C. M.W.=392.957 Elemental analysis:Calcd. C,67.23; H,8.46; N,7.13; Cl,9.02; Found C,66.39; H,8.43; N,7.00;Cl,8.81. I.R. (KBr): 3440; 2950; 1690; 1620; 1605 cm⁻¹ N.M.R. (CDCl₃):δ12.0-11.2 (s broad, 1H); 8.1-7.9 (m, 1H); 80 MHz 7.3-7.1 (m, 2H);5.4-5.0 (m, 1H); 4.4-3.1 (m, 6H); 3.1-2.8 (m, 8H); 2.8-2.5 (m, 2H);2.4-1.8 (m, 2H); 1.7-1.2 (m, 4H); 0.9 (ds, 6H).

EXAMPLE 7

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(1-dimethylamino)ethylpiperidine hydrochloride Diastereoisomer A.

Prepared as described in Ex. No. 1, from 1.95 g (12.50 mmoles) of(±)-2-(1-dimethylamino)ethyl piperidine [1/1 diastereo-isomericmixture], 1.8 g (13.0 mmoles) of anhydrous potassium carbonate and 3.3 g(14.83 mmoles) of crude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetylchloride in 60 ml of dry chloroform. The crude mixture was purified by230-400 mesh silica gel flash column chromatography, eluting with amixture of AcOEt/28% NH₄ OH, 50:0.3 respectively, to afford 0.8 g of theless polar free base, which was dissolved in 25 ml of acetone and thesolution brought to acidic pH with HCl/Et₂ O. The precipitate wasfiltered, washed and dried, to yield 600 mg of the title compound.

C₂₁ H₃₀ N₂ O₂.HCl M.P.=199°-200 ° C. M.W.=378. 931 Elemental analysis:Calcd. C,66.56; H,8.25; N,7.39; Cl,9.36; Found C,65.35; H,8.23 N,7 20;Cl,9.41. I.R. (KBr): 3450; 2940; 1680; 1625; 1605; 1435 cm⁻¹

EXAMPLE 8

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(1-dimethylamino)ethylpiperidine hydrochloride Diastereoisomer B.

Continuing the elution of the chromatographic column of the previousexample with a mixture of AcOEt/MeOH/28% NH₄ OH, 50:1.5:0.4respectively, 1.1 g of a second free base were obtained. This productwas dissolved in 30 ml of acetone and brought to acidic pH with HCl/Et₂O. The precipitate was filtered, washed and dried, to yield 800 mg ofthe title compound.

C₂₁ H₃₀ N₂ O₂.HCl M.P.=215°-216° C. M.W.=378.931 Elemental analysis:Calcd. C,66.56; H,8.25; N,7.39; Cl,9.36; Found C,65.68; H,8.29; N,7.25;Cl,9.83. I.R. (KBr): 3460; 2940; 1675; 1635; 1615; 1440; 1285; 1235 cm⁻¹

EXAMPLE 9

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-propyl)aminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.14 g (6.69 mmoles) of(2S)-2-(N-methyl-N-propyl)aminomethyl piperidine, 1.00 g (7.24 mmoles)of anhydrous potassium carbonate and 1.53 g (6.87 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 45 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of Et₂ O/MeOH/28%NH₄ OH, 100:1.5:0.6 respectively, to afford 1.0 g of the free base,which was dissolved in 30 ml of ethyl acetate and the solution broughtto acidic pH with HCl/Et₂ O. The precipitate was filtered, washed anddried, to yield 0.8 g of the title compound.

C₂₂ H₃₂ N₂ O₂.HCl M.P.=155°-158° C. M.W.=392.957 [α]_(D) ²⁰ =-56.6 (C=1,MeOH) Elemental analysis: Calcd. C,67.24; H,8.46; N,7.13; Cl,9.02; FoundC,66.69; H,8.41; N,7.02; Cl,9.10. I.R. (KBr): 3440; 2940; 1685: 1635;1605 cm⁻¹

EXAMPLE 10

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-isopropyl)aminomethylpiperidine hydrochloride emihydrate.

Prepared as described in Ex. No. 1, from 1.1 g (6.46 mmoles) of2S)-2-(N-methyl-N-isopropyl)aminomethyl piperidine, 1.0 g (7.24 mmoles)of anhydrous potassium carbonate and 1.9 g (8.54 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:6:0.5 respectively, to afford 1.4 g of the free base, whichwas dissolved in 30 ml of ethyl acetate, containing 20% of diethylether, and the solution brought to acidic pH with HCl/Et₂ O. Theprecipitate was filtered, washed and dried, to yield 1.2 g of the titlecompound.

C₂₂ H₃₂ N₂ O₂.1/2 H₂ O M.P.=159°-160° C. M.W.=401.965 [α]_(D) ²⁰ =-62.1(C=1, MeOH) Elemental analysis: Calcd C,65 73; H,8.53; N,6.97; Cl,8.82Found C,65.70; H,8.41; N,6.87; Cl,9.13. I.R. (KBr): 3550; 3480; 2940;1680; 1635; 1605 cm⁻¹ N.M.R. (CDCl₃): δ11.30 (s broad, 1H); 8.00 (d,1H); 7.10-7.30 (80 MHz) (m, 2H): 5.10-5.40 (m, 1H); 3.20-4.50 (m, 6H);2.40-3.10 (m, 8H); 1.10-2.30 (m, 14H).

EXAMPLE 11

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-allyl-N-methyl)aminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.15 g (6.80 mmoles) of(2S)-2-(N-allyl-N-methyl)aminomethyl piperidine, 1.00 g (7.24 mmoles) ofanhydrous potassium carbonate and 1.67. g (7.50 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 35 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of EtOAc/n-hexane6:4, containing 0.2% of 28% NH₄ OH, to afford 0.5 g of the free base,which was dissolved in 15 ml of ethyl acetate and the solution broughtto acidic pH with HCl/Et₂ O. The precipitate was filtered, washed anddried, to yield 0.35 g of the title compound.

C₂₂ H₃₀ N₂ O₂.HCl M.P.=183°-184° C. M.W.=390.941 [α]_(D) ²⁰ =-60.3 (C=1,MeOH) Elemental analysis: Calcd. C,67.59; H,7.74; N,7.16; Cl,9.07; FoundC,67.31; H,7.83; N,7.06; Cl,9.02. I.R. (KBr): 3430; 2940; 1685; 1625;1605 cm⁻¹

EXAMPLE 12

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclopropyl-N-methyl)aminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 1.4 g (8.32 mmoles) of(2S)-2-(N-cyclopropyl-N-methyl)aminomethyl piperidine, 1.2 g (8.69mmoles) of anhydrous potassium carbonate and 2.0 g (8.98 mmoles) ofcrude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drymethylene chloride. The crude product was purified by 230-400 meshsilica gel flash column chromatography, eluting with a mixture ofEtOAc/n-hexane 6:4, containing 0.2% of 28% NH₄ OH, to afford 0.85 g ofthe free base, which was dissolved in 20 ml of ethyl acetate and thesolution brought to acidic pH with HCl/Et₂ O. The precipitate wasfiltered, washed and dried, to yield 0.65 g of the title compound.

C₂₂ H₃₀ N₂ O₂.HCl M.P.=172°-174° C. M.W.=390.941 [α]_(D) ²⁰ =-55.6 (C=1,MeOH) Elemental analysis: Calcd. C,67.59; H,7.99; N,7.17; Cl,9.07; FoundC,67.65; H,7.98; N,7.98; Cl,9.04. I.R. (KBr): 3440; 2930: 1675; 1625;1605 cm⁻¹

EXAMPLE 13

(2S)-1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-tbutyl)aminomethylpiperidine hydrochloride.

Prepared as described in Ex. No. 1, from 0.41 g (2.23 mmoles) of(2S)-2-(N-methyl-N-tbutyl)aminomethyl piperidine, 0.4 g (2.90 mmoles) ofanhydrous potassium carbonate and 0.6 g (2.70 mmoles) of crude1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 20 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of EtOAc/n-hexane6:4, containing 0.3% of 28% NH₄ OH, to afford 0.35 g of the free base,which was dissolved in 15 ml of ethyl acetate and the solution broughtto acidic pH with HCl/Et₂ O. The very hygroscopic material was filtered,washed and dried, to yield 0.25 g of the title compound.

C₂₃ H₃₄ N₂ O₂.HCl M.P.=110°-114° C. M.W.=406.983 [α]_(D) ²⁰ =-19.7 (C=1,MeOH) I.R. (KBr): 3450; 2940; 1675; 1630; 1605 cm⁻¹

EXAMPLE 14

(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl4,4-dimethyipiperidineL(+) tartrate.

2.2 g (6.2 mmoles) of the compound of Ex. No. 5 (as free base) weredissolved in 30 ml of abs. ethanol. 0.95 g (6.4 mmoles of L(+) tartaricacid, dissolved in 30 ml of abs. ethanol, were added to the hot solutionof the free base. After a gentle warming, the solution was filtered andthe less soluble diastereoisomeric salt crystallized on standing. Thesalt was recrystallized from ethanol, up to a constant rotatory power,to give 0.7 g of the title compound.

C₂₂ H₃₂ N₂ O₂.L(+) C₄ H₆ O₆ M.P.=174°-175° C. M.W.=506.580 [α]_(D) ²⁰=+44.5 (C=1, MeOH)

A sample of the L(+) tartrate salt was transformed into the free base bydissolving in acq. NH₃ solution, extracting with diethyl ether andevaporating the solvent in vacuo. The obtained free base was dissolvedin ethyl acetate and transformed into the hydrochloride salt bytreatment with HCl/Et₂ O.

The salt gave an [α]_(D) ²⁰ =+47.0 (C=1, MeOH) The I.R. and N.M.R.spectra were identical to those obtained for the racemate.

EXAMPLE 15

(-)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-4,4-dimethylpiperidineD(-) tartrate.

The mother liquors of the first crystallization of Ex. No. 14 wereevaporated in vacuo to dryness. The residue was treated with acq. NH₃solution and extracted with diethyl ether to afford 1.12 g (3.14 mmoles)of the enriched free base, which was dissolved in 30 ml of abs. ethanol.0.47 g (3.14 mmoles) of D(-) tartaric acid, dissolved in abs. ethanol,were added to the warm solution and the diastereoisomeric saltcrystallized on standing. The salt was recrystallized from ethanol, upto a constant rotatory power, to give 0.5 g of the title compound.

C₂₂ H₃₂ N₂ O₂.D(-) C₄ H₆ O₆ M.P.=173°-174° C. M.W.=506.580 [α]_(D) ²⁰=-43.5 (C=1, MeOH)

A sample of the D(-) tartrate was transformed into the correspondinghydrochloride salt following the same procedure described in the Ex. No.14. This salt gave an [α]_(D) ²⁰ =-46.2 (C=1, MeOH) The I.R. and N.M.R.spectra were identical to those obtained for the racemate.

EXAMPLE 16

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-propargyl)aminomethylpiperidine hydrochloride

Prepared as described in Ex. No. 1, from 700 mg (4.21 mmoles) of crude(2S)-2-(N-methyl-N-propargyl)aminomethyl piperidine, 600 mg (4.34mmoles) of anhydrous potassium carbonate and 1.08 g (4.83 mmoles) ofcrude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 30 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of ethylacetate/n-hexane 8:2, containing 0.5% of 28% NH₄ OH, to afford 250 mg ofthe free base, which was dissolved in 15 ml of ethyl acetate containing20% of ethyl ether and the solution brought to acidic pH with HCl/Et₂ O.The precipitate was filtered, washed and dried, to yield 100 mg of thetitle compound.

C₂₂ H₂₈ N₂ O₂.HCl M.P.=169°-170° C. M.W.=388.925 I.R. (KBr): 3430; 2940;1680; 1630; 1608 cm⁻¹ N.M.R. (CDCl₃): δ11.80 (s broad, 1H); 8.00 (d,1H); 7.15-7.30 80 MHZ (m, 2H); 4.20-5.40 (m, 2H); 3.10-4.15 (m, 6H);2.80-3.05 (m, 5H); 2.50-2.70 (m, 3H); 1.90-2.30 (m, 3H); 1.30-1.80 (m,6H).

EXAMPLE 17

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclobutyl-N-methyl)aminomethylpiperidine hydrochloride

Prepared as described in Ex. No. 1, from 1.7 g (9.32 mmoles of(2S)-2-(N-cyclobutyl-N-methyl)aminomethyl piperidine, 1.5 g (10.86mmoles) of anhydrous potassium carbonate and 2.08 g (9.35 mmoles) ofcrude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 50 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with ethyl acetate containing 0.6%of 28% NH₄ OH, to afford 1.7 g of the free base, which wasrechromatographed on silica gel, eluting with a mixture of CH₂ Cl₂/MeOH/28% NH₄ OH, 94:15:0.3 respectively, to afford 1.4 g of the purefree base. The compound was dissolved in 30 ml of ethyl acetate and thesolution brought to acidic pH with HCl/Et₂ O. The precipitate wasfiltered, washed and dried, to yield 1.3 g of the title compound.

C₂₃ H₃₂ N₂ O₂.HCl M.P.=184°-186° C. M.W.=404.967 [α]_(D) ²⁰ =-58.8 (C=1,MeOH) Elemental analysis: Calcd.: C,68.21; H,8.21; N,6.92; Cl,8.76;Found: C,68.46; H,8.18; N,6.59; Cl,8.30. I.R. (KBr): 3440; 2940; 1685;1625; 1605 cm⁻¹

EXAMPLE 18

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclopentyl-N-methyl)aminomethylpiperidine hydrochloride .1/4 H₂ O

Prepared as described in Ex. No. 1, from 1.70 g (8.66 mmoles) of(2S)-2-(N-cyclopentyl-N-methyl)aminomethyl piperidine, 1.37 g (9.92mmoles) of anhydrous potassium carbonate and 2.19 g (9.80 mmoles) ofcrude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 50 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with ethyl acetate containing 0.6%of 28% NH₄ OH, to afford 1.90 g of the pure free base, which wasdissolved in 40 ml of ethyl acetate and the solution brought to acidicpH with HCl/Et₂ O. The precipitate was filtered, washed and dried, toyield 1.55 g of the title compound.

C₂₄ H₃₄ N₂ O₂.1/4 H₂ O M.P.=126°-129° C. M.W.=423.497 [α]_(D) ²⁰ =-62.1(C=1, MeOH) Elemental analysis: Calcd.: C,68.06; H,8.45: N,6.61;Cl,8.37; Found: C,68.11; H,8.42; N,6.54; Cl,8.3 I.R. (KBr): 3450; 2940;1680; 1630; 1605 cm⁻¹

EXAMPLE 19

(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclopropylmethyl-N-methyl)aminomethylpiperidine hydrochloride

Prepared as described in Ex. No. 1, from 1.35 g (7.40 mmoles) of2S)-2-(N-cyclopropylmethyl-N-methyl)aminomethyl piperidine 1.22 g (8.84mmoles) of anhydrous potassium carbonate and 1.97 g (8.81 mmoles) ofcrude 1-oxo-3,4-dihydro-(2H)-napht-6-yl acetyl chloride in 40 ml of drychloroform. The crude product was purified by 230-400 mesh silica gelflash column chromatography, eluting with a mixture of CH₂ Cl₂ /MeOH/28%NH₄ OH, 94:2.5:0.4 respectively, to afford 1.4 g of the title compound.

C₂₃ H₃₂ N₂ O₂.HCl M.P.=148°-150° C. M.W.=404.967 [α]_(D) ²⁰ =-54.8 (C=1,MeOH) I.R. (KBr): 3440; 2940; 1685; 1625; 1605; 1425 cm⁻¹ N.M.R.(CDCl₃): δ11.80 (s broad, 1H); 8.00 (d, 1H); 7.10-7.30 80 MHz (m, 2H);5.10-5.45 (m, 1H); 2.80-4.25 (m, 13H); 2.60 (t, 2H); 1.90-2.30 (m, 2H);1.05-1.85 (m, 7H); 0.60-0.90 (m, 2H); 0.30-0.55 (m, 2H).

                                      TABLE I                                     __________________________________________________________________________     ##STR7##                                                                                                    MOLECULAR   MELTING   [α]D.sup.20        Example N°                                                                    R1   R2      R3  R4  R5 FORMULA     POINT (°C.)                                                                   *  (C = 1,                  __________________________________________________________________________                                                         MeOH)                     1     CH.sub.3                                                                           CH.sub.3                                                                              H   H   H  C.sub.20 H.sub.28 N.sub.2 O.sub.2.HCl                                                     208-210                                                                              S  -64.0                     2     CH.sub.3                                                                           CH.sub.2 CH.sub.3                                                                     H   H   H  C.sub.21 H.sub.30 N.sub.2 O.sub.2.HCl                                                     163-165                                                                              S  -62.5                     3     CH.sub.2 CH.sub.3                                                                  CH.sub.2 CH.sub.3                                                                     H   H   H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl                                                     136-137                                                                              S  -61.6                     4     CH.sub.3                                                                           CH.sub.3                                                                              3-CH.sub.3                                                                        3-CH.sub.3                                                                        H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl                                                     253-255                                                                              R, S                                                                             --                        5     CH.sub.3                                                                           CH.sub.3                                                                              4-CH.sub.3                                                                        4-CH.sub.3                                                                        H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl                                                     214-216                                                                              R, S                                                                             --                        6     CH.sub.3                                                                           CH.sub.3                                                                              5-CH.sub.3                                                                        5-CH.sub.5                                                                        H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl                                                     188-190                                                                              R, S                                                                             --                        7 DIAST. A                                                                          CH.sub.3                                                                           CH.sub.3                                                                              H   H   CH.sub.3                                                                         C.sub.21 H.sub.30 N.sub.2 O.sub.2.HCl                                                     199-200                                                                              R, S                                                                             --                        8 DIAST. B                                                                          CH.sub.3                                                                           CH.sub.3                                                                              H   H   CH.sub.3                                                                         C.sub.21 H.sub.30 N.sub.2 O.sub.2.HCl                                                     215-216                                                                              R, S                                                                             --                        9     CH.sub.3                                                                           CH.sub.2 CH.sub.2 CH.sub.3                                                            H   H   H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl                                                     155-158                                                                              S  -56.6                    10     CH.sub.3                                                                            ##STR8##                                                                             H   H   H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.HCl.1/2H.                                   sub.2 O     159-160                                                                              S  -62.1                    11     CH.sub.3                                                                           CH.sub.2 CHCH.sub.2                                                                   H   H   H  C.sub.22 H.sub.30 N.sub.2 O.sub.                                                          183-184                                                                              S  -60.3                    12     CH.sub.3                                                                            ##STR9##                                                                             H   H   H  C.sub.22 H.sub.30 N.sub.2 O.sub.2.HCl                                                     172-174                                                                              S  -55.6                    13     CH.sub.3                                                                            ##STR10##                                                                            H   H   H  C.sub.23 H.sub.34 N.sub.2 O.sub.2.HCl                                                     110-114                                                                              S  -19.7                    14     CH.sub.3                                                                           CH.sub.3                                                                              CH.sub.3                                                                          CH.sub.3                                                                          H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.                                                        174-175                                                                              R  +44.5                                                   L(+) C.sub.4 H.sub.6 O.sub.6                   15     CH.sub.3                                                                           CH.sub.3                                                                              CH.sub.3                                                                          CH.sub.3                                                                          H  C.sub.22 H.sub.32 N.sub.2 O.sub.2.                                                        173-174                                                                              S  -43.5                                                   D(-) C.sub.4 H.sub.6 O.sub.6                   16     CH.sub.3                                                                           CH.sub.3 CCH                                                                          H   H   H  C.sub.22 H.sub.28 N.sub.2 O.sub.2.HCl                                                     169-170                                                                              S  --                       17     CH.sub.3                                                                            ##STR11##                                                                            H   H   H  C.sub.23 H.sub.32 N.sub.2 O.sub.2.HCl                                                     184-186                                                                              S  -58.8                    18     CH.sub.3                                                                            ##STR12##                                                                            H   H   H  C.sub.24 H.sub.34 N.sub.2 O.sub.2.HCl.1/4H.                                   sub.2 O     126-129                                                                              S  -62.1                    19     CH.sub.3                                                                            ##STR13##                                                                            H   H   H  C.sub.23 H.sub.32 N.sub.2 O.sub.2.HCl                                                     148-150                                                                              S  -54.8                    __________________________________________________________________________

The pharmacological activity of the compounds of this invention isillustrated by the mouse writhing test, described as follows:

P-phenylquinone-induced abdominal writhing test in mice

The methodology employed is based on that described by Sigmund et al,Proc. Soc. Exptl. Biol. 95, 729/1957, modified by Milne and Twomey,Agents and Actions, 10, 31/1980.

Male Charles River mice (Swiss Strain), 25-36 g body weight, were used.Animals were allowed food and water ad libitum and were randomized intogroups of 10 prior to experimentation. Test compounds were dissolved ineither distilled water or distilled water plus 0.1M AMS, andadministered by the subcutaneous route in a final volume of 10 ml/Kg.Control animals received 10 ml/Kg of the appropriate vehicle alone.Following a pretreatment period of 20 min., mice were injectedintraperitoneally with p-phenylquinone, 2 mg/Kg at 37° C. in a finalvolume of 10 mg/kg. Next, the mice were placed, in groups of 3, in acompartmented perspex box maintained at room temperature and wereobserved for a period of 8 min. During this period the number ofabdominal writhing responses per animal were recorded where writhingconsists of an intermittent contraction of the abdomen associated withhind leg extension.

The degree of antinociceptive protection afforded by the test compoundwas determined as the mean number of writhing responses observed in thetreated group (T) expressed as a percentage of the mean number ofwrithing responses in the control group (C) according to the followingformula:

    [1-(T/C]×100%=% graded protection

RECEPTOR AFFINITY STUDY

Tissue Preparation

Radio receptor binding to kappa site is performed on fresh guinea pigbrain homogenates prepared according to Kosterlitz (1981).

Whole brain without cerebellum is homogenized in 50 mM Tris-buffer (pH7.4 at 0° C.) and centrifuged at 49,000×g for 10 min.

The pellet is then resuspended in the same buffer, incubated at 37° C.for 45 min and centrifuged again.

1.9 ml of the final homogenate (1:100 in Tris pH 7.4, 0° C.) is used forthe binding assay.

Binding to kappa sites

The binding to the kappa sites is performed using a tritiated kappaselective compound. Final homogenate with solutions of the cold ligandand of the labelled ligand is incubated for 40 min at 25° C., filteredthrough Whatman GF/C glass filter discs and washed. The radioactivitybound to the filters is counted by liquid scintillationspectrophotometry.

The non-specific binding is determined in the presence of 500 nM of thebenzomorphan non-selective compound Mr 2266.

Binding to mu sites (Magnan J., 1982)

³ H[D-Ala², MePhe⁴, Gly-ol⁵ ] Enkephalin (³ H-DAGO), an enkephalinanalogue that binds selectively to mu receptor, is added to thebiological substrate and incubated at 25° C. for 40 min, filteredthrough Whatman GF-C and washed with ice-cold Tris-buffer.

The filters are then dried, solubilized in Filtercount and theradioactivity monitored. Non-specific binding is determined in thepresence of 10⁻⁶ M naloxone.

Binding to delta sites (Magnan J., 1982)

For binding experiments, ³ H-DADLE, which binds to mu and delta sites,is used in the presence of 30 nM of unlabelled DAGO to prevent mubinding. A concentration of radioligand near KD is used in the bindingassays evaluating compounds of the invention. Non-specific binding isdetermined by addition of Mr 2266 2.5 μM.

The tubes are incubated for 40 min at 25° C. and bound ligand isseparated from free by filtration through Whatman GF/C filters. Thelevel of bound radioactivity of the filters is measured by liquidscintillation after solubilization in Filtercount.

The equilibrium dissociation constant (FD) and the maximum bindingcapacity (Bmax) are determined from the analysis of saturation curves,while the inhibition constant (Ki) is determined from the analysis ofcompetition experiments (Hill 1910; Scatchard 1949; Cheng and Prusoff1973; Gillan et al 1980).

Published references are summarized as follows:

Hill, A. V. (1910): J. Physiol. 40, IV-VIII

Scatchard G. (1949): Ann. N.Y. Acad. Sci. 51, 660-674

Cheng and Prusoff W. H. (1973): Biochem. Pharmac. 22, 3099-3102

Gillan M. C. G., Kosterlitz H. W. and Paterson S. Y. (1980): Br. J.Pharmac. 70, 481-490

Kosterlitz H. W., Paterson S. Y. and Robson L. E. (1981): Br. J.Pharmac. 73, 939-949

Magnan J., Paterson S. Y., Tavani A. and Kosterlitz H. W. (1982): Arch.Pharmacol. 319, 197-205.

                  TABLE 11                                                        ______________________________________                                        Pharmacological data                                                                   ANALGESIA                                                                     MOUSE WRITHING KAPPA BRAIN                                                    (GRADED)       RECEPTOR BINDING                                      Example N°                                                                      ED50 mg/kg s.c.                                                                              Ki nM                                                 ______________________________________                                         1       0.154          47.0                                                   2       0.061          10.3                                                   3       0.427          80.3                                                   5       0.377          65.0                                                   6       0.641          88.7                                                   9       0.221          10-50                                                 10       0.078           2.87                                                 11       0.130          ca 50                                                 12       0.141          50                                                    15       0.115          22.9                                                  16       0.056          --                                                    17       0.127          --                                                    18       0.210          --                                                    ______________________________________                                    

Mu and delta binding affinities for the above Examples were found tobe >1000 nM.

We claim:
 1. A compound, or a solvate or salt thereof, of formula (I):##STR14## in which: R₁ and R₂ are each linear or branched C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₄₋₆ cycloalkylalkyl, C₃₋₄ alkenyl, C₃₋₆ cycloalkenylor C₃₋₄ alkynyl,R₃ and R₄ are identical, and each is hydrogen or C₁₋₄alkyl; and R₅ is hydrogen or C₁₋₃ alkyl.
 2. A compound according toclaim 1, in which R₃ and R₄ are both C₁₋₄ alkyl and are bonded to thesame carbon atom of the piperidine ring.
 3. A compound according toclaim 1 in which each of R₁ and R₂ is methyl, ethyl, propyl, isopropyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,allyl or propynyl.
 4. A compound according to claim 1 in which R₃ and R₄are together 3,3 gem-dimethyl, 4,4 gem-dimethyl or 5,5 gem-dimethyl. 5.A compound according to claim 1 in which R₅ is hydrogen or methyl.
 6. Acompound according to claim 1 whichis:(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethyl-aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-ethyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-diethylamino-methylpiperidine;(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylamino-methyl-3,3-dimethylpiperidine;(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylamino-methyl-4,4-dimethylpiperidine;(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylamino-methyl-5,5-dimethylpiperidine;(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(1-dimethylamino)ethylpiperidine Diastereoisomer A;(±)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(1-dimethylamino)ethylpiperidine Diastereoisomer B;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-propyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-isopropyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-allyl-N-methyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclopropyl-N-methyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-butyl)aminomethylpiperidine;(+)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-4,4-dimethylpiperidineL(+)tartrate;(-)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-dimethylaminomethyl-4,4-dimethylpiperidineD(-)tartrate;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-methyl-N-propargyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclobutyl-N-methyl)aminomethylpiperidine;(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclopentyl-N-methyl)aminomethylpiperidine; or(2S)-1-[1-oxo-3,4-dihydro-(2H)-napht-6-yl]acetyl-2-(N-cyclo-propylmethyl-N-methyl)aminomethylpiperidine.
 7. A pharmaceutical composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable carrier.
 8. Amethod for the treatment of pain and/or cerebral ischaemia in mammals,which comprises administering to the mammal in need of said treatment aneffective amount of a compound according to claim 1.